Currently, there are 42 million AIDS cases worldwide, with a majority present in the third world; 3.1 million deaths can be attributed to HIV and AIDS in 2002 alone. There is no vaccine against HIV, and AIDS, if untreated, will lead to the death of over 95% of infected individuals 10 years post-infection. In the last few years, significant therapeutic breakthroughs have been made. Mixtures of drugs directed at viral protease and reverse transcriptase have proven to be effective in lowering plasma viral load and slowing the progression of AIDS. However, these cocktail therapies have serious side effects and are financially unattainable by a majority of the HIV-infected population. In addition, resistant strains of HIV are emerging that contribute to the decline in efficacy of these drug mixtures. Thus, new and cost-effective drugs, preferably directed at different viral proteins, need to be developed to keep ahead of this viral pandemic. To accomplish this goal, we have screened over 10,000 extracts derived from the traditional and novel fractionations of a unique marine microorganism library for activity against HIV-1 in cytoprotection and cytotoxicity assays. The marine microorganisms were fractionated by the traditional butanol and aqueous extraction methods as well as a novel SuperFluids TM fractionation technique that yields partially purified fractions of increasing polarity. We have identified 305 extracts "hits," for a hit rate of 2.9%, that are effective against HIV-1. We propose to prioritize and confirm 170 of these results in first a cytoprotection assay and second in a direct viral reduction assay. A preliminary determination of the active extracts' virus-specific target molecule will be made. High priority extract "hits" that are effective against several primary isolates will be subjected to bioassay guided fractionation, chemical structure elucidation, and dereplication. Potential Commercial Applications. The discovery and development of novel and cost-effective anti-HIV drugs from a readily fermentable marine microorganism resource will be of tremendous benefit to the over 42 million AIDS patients worldwide. Such drugs will become commercially important in that they could emulate the contribution that penicillin played in the field of antibiotics.